Zare Abdolhossein, Salehi Saeede, Bader Jakob M, Wiessler Anna-Lena, Prokesch Manuela, Albrecht Vincent, Villmann Carmen, Mann Matthias, Briese Michael, Sendtner Michael
Institute of Clinical Neurobiology, University Hospital Wuerzburg, Würzburg, Germany.
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Munich, Germany.
Transl Neurodegener. 2025 Jul 29;14(1):39. doi: 10.1186/s40035-025-00499-0.
Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy.
We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry.
Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations.
Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.
大脑中高磷酸化tau蛋白的病理性沉积与阿尔茨海默病（AD）的病程密切相关。tau蛋白病理改变发生在受影响神经元的轴突中，因此从轴突中清除tau蛋白可能是一种早期干预策略。
我们研究了RNA结合蛋白hnRNP R在从hnRNP R基因敲除小鼠培养的神经元中Mapt mRNA的轴突定位和局部翻译中的作用。将hnRNP R基因敲除小鼠与AD小鼠模型5×FAD小鼠杂交，并评估hnRNP R缺失对磷酸化tau蛋白和淀粉样β斑块沉积的影响。我们设计了反义寡核苷酸（MAPT-ASO）来阻断hnRNP R与Mapt mRNA的结合。用MAPT-ASO处理培养的小鼠和人类神经元，并对轴突中的Mapt mRNA和tau蛋白水平进行定量。将MAPT-ASO脑室内注射到5×FAD小鼠中，随后对其大脑中的磷酸化tau蛋白聚集体和淀粉样β斑块进行定量。通过质谱法测量用MAPT-ASO处理的5×FAD小鼠大脑中的蛋白质变化。
从hnRNP R基因敲除小鼠培养的原代神经元的轴突中Mapt mRNA和tau蛋白减少，但细胞体中未减少。缺乏hnRNP R的5×FAD小鼠大脑在皮质和海马中含有较少的磷酸化tau蛋白聚集体和淀粉样β斑块。用MAPT-ASO处理神经元以阻断hnRNP R与Mapt的结合同样降低了轴突tau蛋白水平。脑室内注射MAPT-ASO降低了5×FAD小鼠大脑中的磷酸化tau蛋白和斑块负荷，并预防了神经退行性变，同时挽救了蛋白质组改变。
因此，选择性降低轴突中的tau蛋白代表了治疗AD和其他tau蛋白病的一种创新治疗前景。
